New HIV vaccine strategy strengthens, lengthens immunity in primates

Investigators at the Stanford University School of Medicine and several other institutions have shown that a new type of vaccination can substantially enhance and sustain protection from HIV.

A paper describing the vaccine, which was given to monkeys, will be published online May 11 in Nature Medicine. The findings carry broad implications for immunologists pursuing vaccines for the coronavirus and better vaccines for other diseases, said Bali Pulendran, PhD, professor of pathology and of microbiology and immunology at Stanford.

The key to the new vaccine’s markedly improved protection from viral infection is its ability — unlike almost all vaccines now in use — to awaken a part of the immune system that most current vaccines leave sleeping.

“Most vaccines aim at stimulating serum immunity by raising antibodies to the invading pathogen,” said Pulendran, referring to antibodies circulating in blood. “This vaccine also boosted cellular immunity, the mustering of an army of immune cells that chase down cells infected by the pathogen. We created a synergy between these two kinds of immune activity.”

Pulendran, the Violetta L. Horton Professor II, shares senior authorship of the study with Rama Amara, PhD, professor of microbiology and immunology at Yerkes Primate Research Center at Emory University; Eric Hunter, PhD, and Cynthia Derdeyn, PhD, professors of pathology and lab medicine at Emory; and David Masopust, PhD, professor of microbiology and immunology at the University of Minnesota. The lead authors are Prabhu Arunachalam, PhD, a postdoctoral scholar at Stanford; postdoctoral scholars Tysheena Charles, PhD, and Satish Bollimpelli, PhD, of Emory; and postdoctoral scholar Vineet Joag, PhD, of the University of Minnesota.

38 million people with AIDS

Some 38 million people worldwide are living with AIDS, the once inevitably fatal disease caused by HIV. While HIV can be held in check by a mix of antiviral agents, it continues to infect 1.7 million people annually and is the cause of some 770,000 deaths each year.

“Despite over three decades of intense research, no preventive HIV vaccine is yet in sight,” Pulendran said. Early hopes for such a vaccine, based on a trial in Thailand whose results were published in 2012, were dashed just months ago when a larger trial of the same vaccine in South Africa was stopped after a preliminary assessment indicated that it barely worked.

Vaccines are designed to arouse the adaptive immune system, which responds by generating cells and molecular weaponry that target a particular pathogen, as opposed to firing willy-nilly at anything that moves.

The adaptive immune response consists of two arms: serum immunity, in which B cells secrete antibodies that can glom onto and neutralize a microbial pathogen; and cellular immunity, in which killer T cells roam through the body inspecting tissues for signs of viruses and, upon finding them, destroying the cells that harbor them.

But most vaccines push the adaptive immune system to fight off infections with one of those arms tied behind its back.

“All licensed vaccines to date work by inducing antibodies that neutralize a virus. But inducing and maintaining a high enough level of neutralizing antibodies against HIV is a demanding task,” Pulendran said. “We’ve shown that by stimulating the cellular arm of the immune system, you can get stronger protection against HIV even with much lower levels of neutralizing antibodies.”

In the new study, he and his colleagues employed a two-armed approach geared toward stimulating both serum and cellular immunity. They inoculated three groups of 15 rhesus macaques over a 40-week period. The first group received several sequential inoculations of Env, a protein on the virus’s outer surface that’s known to stimulate antibody production, plus an adjuvant, a chemical combination often used in vaccines to beef up overall immune response. The second group was similarly inoculated but received additional injections of three different kinds of viruses, each modified to be infectious but not dangerous. Each modified virus contained an added gene for a viral protein, Gag, that’s known to stimulate cellular immunity.

A third group, the control group, received injections containing only the adjuvant.

At the end of the 40-week regimen, all animals were allowed to rest for an additional 40 weeks, then given booster shots of just the Env inoculation. After another rest of four weeks, they were subjected to 10 weekly exposures to SHIV, the simian version of HIV.

Monkeys who received only the adjuvant became infected. Animals in both the Env and Env-plus-Gag groups experienced significant initial protection from viral infection. Notably, though, several Env-plus-Gag animals — but none of the Env animals — remained uninfected even though they lacked robust levels of neutralizing antibodies. Vaccinologists generally have considered the serum immune response — the raising of neutralizing antibodies — to be the defining source of a vaccine’s effectiveness.

Even more noteworthy was a pronounced increase in the duration of protection among animals getting the Env-plus-Gag combination. Following a 20-week break, six monkeys from the Env group and six from the Env-plus-Gag group received additional exposures to SHIV. This time, four of the Env-plus-Gag animals, but only one of the Env-only animals, remained uninfected.

Pulendran said he suspects this improvement resulted from the vaccine-stimulated production of immune cells called tissue-resident memory T cells. These cells migrate to the site where the virus enters the body, he said, and park themselves there for a sustained period, serving as sentinels. If they see the virus again, these cells jump into action, secreting factors that signal other immune-cell types in the vicinity to turn the tissue into hostile territory for the virus.

“These results suggest that future vaccination efforts should focus on strategies that elicit both cellular and neutralizing-antibody response, which might provide superior protection against not only HIV but other pathogens such as tuberculosis, malaria, the hepatitis C virus, influenza and the pandemic coronavirus strain as well,” Pulendran said.

A single dose of an antibody-based treatment can prevent HIV transmission from mother to baby, new nonhuman primate research suggests for the first time. The findings are being published in the journal Nature Communications.

When that single dose is given is key, however. The study found rhesus macaque newborns did not develop the monkey form of HIV, called SHIV, when they received a combination of two antibodies 30 hours after being exposed to the virus.

Delaying treatment until 48 hours, on the other hand, resulted in half of the baby macaques developing SHIV when they were given four smaller doses of the same antibody cocktail. In comparison, the study found macaques that received the current standard HIV treatment — antiretroviral drugs — remained SHIV-free when they started a three-week regimen of that therapy 48 hours after exposure.

“These promising findings could mean babies born to HIV-positive mothers can still beat HIV with less treatment,” said the study’s corresponding’s author, Nancy Haigwood, Ph.D., a professor of pathobiology and immunology in the Oregon Health & Science University School of Medicine, as well as the director at the Oregon National Primate Research Center at OHSU.

This is the first time a single dose of broadly neutralizing antibodies given after viral exposure has been found to prevent SHIV infection in nonhuman primate newborns. Previous research by Haigwood, Ann Hessell, Ph.D., and others showed four doses of antibodies started 24 hours after exposure prevented SHIV infection, with all 10 of the baby primates in that study not having any SHIV virus for six months. Both studies used a combination of two antibodies called PGT121 and VRC07-523.

The new study also suggests a much shorter course of antiretroviral therapy given after virus exposure could prevent HIV transmission to newborns. Human babies born from HIV-positive mothers typically take the drug cocktail — a personalized regimen of multiple drugs taken daily — for about six weeks before being re-tested. If the tests are then positive, they likely need to take HIV drugs for the rest of their lives. But this study showed nonhuman primate newborns didn’t have SHIV after undergoing antiretroviral therapy for just three weeks starting 48 hours after exposure.

HIV-positive women typically take antiretroviral therapy drugs during pregnancy for their own health, as well as to prevent passing the virus onto their developing child. But mother-to-baby transmission sometimes still happens. Children born to HIV-positive mothers also are given antiretroviral therapy to further prevent infection. However, this drug cocktail can have many negative side effects, involves making special liquid formulations for newborns, and researchers worry about antiretroviral therapy’s long-term consequences for development.

Antibodies, however, aren’t toxic and can be modified to last a long time in the body, which reduces treatment frequency. This has led researchers to explore their potential to replace or supplement antiretroviral therapy for newborns with HIV-positive mothers as well as for HIV-positive adults.

Next, Haigwood and colleagues plan to see if different antibodies, or a combination of antibodies and antiretroviral therapy, could be even more effective. They also want to determine if the antibodies they evaluate actually eliminate HIV, or only prevent it from replicating.

The research team has regularly shared their primate research findings with the scientific community, including those involved in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, which is currently leading two trials evaluating a single antibody to treat HIV-exposed newborns.